(1) Field of the Invention
The present invention relates to orally administrable nanoparticle compositions comprising water-soluble drugs with enhanced gastrointestinal absorption rate, and preparation methods thereof. Specifically, the present invention relates to orally administrable nanoparticle compositions having enhanced entrapping rate of water-soluble drugs within nanoparticles composed of lipids and polymers, and being stable against lipases, wherein the nanoparticles are prepared by binding water-soluble drugs with counter-ion substances and adding lipids, polymers, and emulsifiers thereto, and preparation methods thereof.
(2) Description of Related Art
Water-soluble drugs including physiological active agents, protein drugs, have low stability in the gastrointestinal tract and low permeability to the wall of intestinal tract, and thus intravenous injection has been usually used for the drugs. However, intravenous injection is not convenient for most patients in daily lives, and so there have been many efforts to prepare water-soluble drugs into orally administrable formulations.
In case water-soluble drugs are orally administered, the drugs are chemically degraded by action of pH and digestive enzymes whose stability is decreased in the gastrointestinal tract. Thus, most or some parts of the administered drugs could not play their role, and so desired pharmacological effects could not be adequately expressed upon oral administration. Particularly, when the drugs have the decreased solubility or are degraded as pH changes, they loose their potency by the action of gastrointestinal enzymes and show extremely low bioavailability. To solve such problems, there have been studies to prepare formulations for water-soluble drugs, wherein the drugs are not exposed to external chemical environments, e.g. pH or digestive enzymes, by entrapping them within lipids or polymers with high affinity with biological membranes.
For example, orally administrable formulations for water-soluble drugs using W/o or w/o/w emulsion, or liposome are known in the art. However, they have drawbacks of having insufficient drug entrapping rate and low stability.
U.S. Pat. No. 6,004,534 discloses targeting such water-soluble drugs as vaccines or allergens to specific tissues by using targeted liposome therefor. However, it has the problem of having low drug entrapping rate of about 35% in the liposome.
U.S. Pat. No. 6,191,105 discloses preparation of w/o micro-emulsion formulations of insulin polymers. However, the structures of w/o emulsions may be usually disrupted by phase transition upon administration into the body, and thus, drugs dissolved in aqueous phase cannot be protected by oily phase, and are directly exposed to the body.
U.S. Pat. No. 6,277,413 discloses preparation of w/o/w emulsions wherein water-soluble drugs are introduced into the internal aqueous phase. However, in this patent, the particle size of the prepared emulsion is extremely large, 10 to 20 micrometers, and during its preparation, the drugs entrapped in the internal aqueous phase are likely to be released to the external aqueous phase, and thus, the emulsion has low drug entrapping rate.
Korean Patent Laid-open No. 2002-66776 discloses orally administrable formulations of insulin by using monoglyceride lipid carrier of 500 nM or less. However, the carrier consists of only lipid, and thus, may be degraded by lipases in vivo.
Journal of Controlled Release 69, p283-295 (2000) discloses PLGA microspheres containing insulin with less than 50% of drug entrapping rate and more than 5 micrometers of particle size. It has been reported that 100 nanometer-sized particles are absorbed into the intestinal tract 15 to 250 times more than micrometer-sized particles whereas micrometer-sized particles cannot be absorbed into the intestinal tract, and are generally found in the surface of epithelial cells in the intestine [Pharm. Res. 13 (12) p 1838-1845 (1996)]. Therefore, 5 μm-sized PLGA microspheres have only low insulin entrapping rate and deliver insulin less effectively than nanometer-sized particles.
Further, U.S. Pat. No. 5,962,024 discloses dissolving drugs at pH 6.5 or higher by preparing granules or coating the granules with enteric polymers, e.g. hydroxypropyl methylcellulose acetate succinate or methacrylic methyl methacrylate copolymer. However, microspheres formed only from enteric polymers have the drawback that it cannot stabilize drugs unstable in the gastrointestinal tract because the polymers are dissolved in the intestinal tract and the drugs entrapped in the microspheres are exposed in the intestinal tract.
On the other hand, only low fractions of water-soluble drugs are entrapped in carriers composed of lipophilic substances or polymers due to their low affinity with said carriers, and thus, their water-solubility should be lowered by eliminating their charges to enhance drug entrapping rate in the carriers.
WO 94/08599 discloses preparation of complexes wherein insulin is ionically bonded with sodium lauryl sulfate. This preparation method is to dissolve insulin-sodium lauryl sulfate complexes in an organic solvent and use the solution as pulmonary or suppository formulations. However, upon oral administration, the drug is directly exposed to the gastrointestinal tract, and so cannot be maintained stable.
Further, U.S. Pat. No. 5,858,410 discloses nano-particulating water-insoluble drugs by milling and using a microfluidizer, but this has the drawback that this is not suitable for water-soluble drugs unstable in vivo, e.g. protein drugs, because the drugs are directly exposed to in vivo environment.
As described above, for oral administration of water-soluble drugs unstable in vivo including protein drugs, nanoparticles stable against lipases in the gastrointestinal tract should be designed and water-soluble drugs should be entrapped in drug carriers with high efficiency. Technical requirements to achieve these purposes are as follows.
First, to maintain drugs entrapped in nanoparticles stable with no degradation in the gastrointestinal tract, lipid nanoparticles should contain appropriate amounts of polymers to increase their stability in vivo.
Second, entrapping rates of water-soluble drugs in lipophilic carriers should be increased by preparing water-soluble drugs into complexes with counter-ion substances and selecting lipid/polymer systems with the similar affinity thereto to have affinity with lipophilic carriers by modifying water-soluble drugs
Third, particle sizes of lipid/polymer nanoparticles containing complexes of water-soluble drugs and counter-ion materials should be minimized. Also, nanoparticles should be prepared so that the drugs are entrapped within the nanoparticles, and so are not exposed to external environment and are absorbed into the body with maintaining their maximal activity.